Process for preparing 19-nortestosterone derivatives substituted in the 4-position and products of high anabolic activity obtained thereby



3,025,310 PROCESS FOR PREPARING 19-NORTESTOSTER- ONE DERIVATIVESSUBSTITUTED IN TIE 4- POSITION AND PRODUCTS OF HIGH ANA- BDLIC ACTIVITYOBTAINED THEREBY Bruno Camerino, Milan, Italy, assignor to SocietaFarmaceutici Italia, a corporation of Italy No Drawing. Filed Oct. 26,1956, Ser. No. 618,442 Claims priority, application Italy May 21, 1956 4Claims. (Cl. 260-397.4)

This invention relates to the preparation of 19-nortestosteronederivatives substituted in the 4-position.

The compounds of the present invention are defined by the followinggeneral formula:

wherein R represents =0, (H)OH, (H)OR", (CH )OH and (C H )OH, Rrepresents F, Cl and OH, and R" represents an acyl group.

These new compounds were found to possess high anabolic activity onproteins and a relatively low androgen activity. Consequently, they areof great importance in human and veterinary medicine since they may beused in the treatment of decay, osteoporosis, emaciation, convalescence,premature newborns, underdevelopment and senility.

In the copending application of July 19, 1956, Serial No. 598,754, nowabandoned, of which this application is a continuation-in-part, newsteroid hormone derivatives substituted in the 4-position as well as themethod of making them from 4,5-epoxy-3-keto-steroids have beendisclosed. Now I found that, by treating 4,5-epoxy-l9- nortestosteronesof the general formulas wherein R represents =0, (H)OH, (CH )OH and (C H)OH, with mineral acids in an organic solvent at about room temperature,the herein-claimed 4-substituted 19-nortestosterone derivatives areobtained.

The following examples are presented to illustrate the presentinvention, but in no way to limit the scope of the appended claims.

Patented Mar. 13, 1952 lee EXAMPLE 1 4-Chl0r0-19-Nortestosterone AcetateOCOCH;

1.9 g. 19-nortestosterone are dissolved in 120 cc. methanol and treatedfor 1 hour with 3.8 cc. 4/N'NaOH and 7 cc. 36% H 0 The solution is thenacidified with 0.4 cc. acetic acid, diluted with water and extractedwith ethyl acetate. The extract is washed with water, dried anddistilled.

1.9 g. of a mixture of 4fl,5-epoxy-l9-nor-etiocholane- 175-01-3-one and4a,5-epoxy-l9-nor-androstane-17 3-01-3- one obtained in this manner areacetylated with pyridine and acetic anhydride at room temperature for 16hours. After pouring into ice Water, filtering and drying, 1.95 g. of amixture of epoxides acetates are obtained which are recrystallized fromether-petroleum ether and yield 1.42 g.4fi,5-epoxy-l9-nor-etiocholane-l7,B-ol-3-one acetate, M.P. 110-112" C.,[a] =+1O2 (in CHCI 0.5 g. 4,8,5-epoxy-19-nor-etiocholane-l7fl-ol-3-oneacetate are dissolved in 20 cc. chloroform containing 2 cc. ethanol, andtreated for 30 minutes with anhydrous HCl. After Washing with water,drying and distilling, the residue is crystallized from methanol and 0.3g. 4-chlorol9-nortestosterone acetate are obtained, M.P. 168-170 C.,kmax 255 m 5:13.980.

I EXAMPLE 2 4-Chl0r0-19-N0rtestosterone Cyclopentylpropionate o 0 0 0H=0H, l 1

l Cl

having Amax 257 m and E=12.800,- is obtained.

EXAMPLE 3 I g-Nor-A -A ndrstene-4 ,1 7fi-D fol-3 -One-1 7-A cetate I OH0.5 g. 4 S,5-epoxy-l9-nor-etiocholane-17fl-ol-3-one acetate aredissolved in 2.5 cc. acetic acid and a 1 cc. solution of H 80 in aceticacid (ratio 1:4 by volume) and left standing overnight at roomtemperature. The solution is diluted with ice and extracted withbenzene. The extract is washed with alkali and water, and is dried anddistilled. The residue is taken up with methanol and yields 0.35 g.19-nor-A -androstene-4,17fl-diol-3-one-17- acetate, M.P. 210-2l2 C.,Mnax 276 my, 5:12.670.

EXAMPLE 4 4 -F l uoro-I 9-N0rtestoste r0ne Acetate 0.5 g. 4;,5-epoxy-19-nor-etiocholane-17 3-ol-3-one-acetate are dissolved in cc.chloroform and 1.5 cc. absolute ethanol and treated for 50 minutes witha stream of anhydrous HF. An amount of a 2 N NaOH solution, insufficientto neutralize the hydrofluoric acid, is then added, the resultingprecipitate is separated, washed with water, dried and the solvent isdistilled off.

Upon crystallization from ether-petroleum ether, 4-fiuoro-l9-nortestosterone acetate is obtained, Xmax 241 m 6:12.200.

EXAMPLE 5 4 -Cl1lor0-1 7a-Methyl-19-N0rtest0sterone17a-methyl-19-nortestosterone is epoxidized by treating with alkalinehydrogen peroxide as described in Example 1. The crude epoxide thusobtained is dissolved in a chloroform-ethanol mixture and treated withanhydrous Hill as in Example 1. 4-chloro-17a-methyl-19-nortestosteroneis obtained, Amax 256 m e=13.400.

EXAMPLE 6 4 C11 101 7a-Ezhyl-19-N0rtest0ster0ne EXAMPLE 7Pharmacological Activity 0 4-ChI0r0-19-Nortestoster0ne-Cyclopentylpropionate 4-chloro-19-nortestosterone cyclopentylpropionate,injected into impuberal rats, castrated according to the method ofHershberger et al. (Proc. Soc. Expt. Biol. and Med. 83, 175, (1953)), indoses of 250 7, increases the weight of the levator ani muscle from 11.7mg. to 32 mg., while 19-nortestosterone cyclopentylpropionate increasesthe weight of this muscle from 11.7 mg. to 40.1 mg.

4-chloro-19-nortestosterone cyclopentylpropionate in creases theprostate weight from 8.8 to 21.4 mg. (19- nortestosteronecyclopentylpropionate from 8.8 to 44.1 mg.) and the weight of theseminal bladders from 5.6 to 19.7 mg. (19-nortestosteronecyclopentylpropionate from 5.6 to 42.2 mg).

Consequently, the ratio between the anabolic activity and the androgenactivity calculated according to Hershberger et al., is 1.61 for the4-chloro-l9-nortestosterone cyclopentylpropionate and 0.80 for the19-nortestosterone cyclopentylpropionate.

I claim:

1. 19nor-A -androstene-4,17-beta-diol-3-one-l7-acetate.

2. A process of making 19-nor-A-androstene-4,17-betadiol-3-one-17-acetate, comprising treating 4 beta,S-epoxy- 19-nor-etiocholane-17-beta-ol-3-one acetate, dissolved inacetic acid, with sulfuric acid at about room temperature.

OCOR

in which the COR radical is an acyl radical derived from a non-toxic,stable, pharmaceutically acceptable acid, the acid having not more thaneight carbon atoms, the R group being a saturated hydrocarbon radical.

4. A process of making a l7-ester of 4,-hydroxy-19- 6 nortestosterone ofthe formula defined in claim 15, com- 2,762,818 Levy et al. Sept. 11,1956 prising treating the corresponding 17-ester of 4,5-epoxy- 2,842,571Camerino et a1. July 8, 1958 19-norandrostane-17,6-01-3-one, dissolvedin acetic acid, 2,885,398 Julian et al. May 5, 1959 with sulfuric acidat about room temperature. 2,908,682 Bible et al. Oct. 13, 1959 5References Cited in the file of this patent OTHER REFERENCES UNITEDSTATES PATENTS Camerino et al.: J.A.C.S., vol. 78, pp. 3540-41, July2,738,348 Colton Mar. 13, 1956 20,1956-

3. A CHEMICAL COMPOUND HAVING HIGH ANABOLIC ACTIVITY ON PROTEINS ANDRELATIVELY LOW ANDROXY ACTITIVY, SAID COMPOUND BEING A 17-ESTER OF4-HYDROXY-19-NORTESTOSTERONE OF THE GENERAL FORMULA